Vaping during pregnancy: a systematic review of health outcomes

Introduction Smoking during pregnancy is harmful to maternal and child health. Vaping is used for smoking cessation but evidence on health effects during pregnancy is scarce. We conducted a systematic review of health outcomes of vaping during pregnancy. Methods We searched six databases for maternal/fetal/infant outcomes and vaping, including quantitative, English language, human studies of vaping during pregnancy, to November 10th, 2023. We assessed study quality with the Mixed-Methods Appraisal Tool. We focused on comparisons of exclusive-vaping with non-use of nicotine and tobacco products and with smoking. Presentation is narrative as the studies were of insufficient quality to conduct meta-analysis. Results We included 26 studies, with 765,527 women, with one randomised controlled trial (RCT) comparing vaping and nicotine replacement therapy for smoking cessation, 23 cohort studies and two case–control studies. While the RCT met 4/5 quality criteria, the quality of the cohort studies and case–control studies was poor; none adequately assessed exposure to smoking and vaping. For studies comparing exclusive-vaping with ‘non-use’, more reported no increased risk for vaping (three studies) than reported increased risk for maternal pregnancy/postpartum outcomes (one study) and for fetal and infant outcomes (20 studies no increased risk, four increased risk), except for birth-weight and neurological outcomes where two studies each observed increased and no increased risk. When the RCT compared non-users with those not smoking but vaping or using NRT, irrespective of randomisation, they reported no evidence of risk for vaping/NRT. For studies comparing exclusive-vaping and exclusive-smoking, most studies provided evidence for a comparable risk for different outcomes. One maternal biomarker study revealed a lower risk for vaping. For small-for-gestational-age/mean-birth-centile equal numbers of studies found lower risk for vaping than for smoking as found similar risk for the two groups (two each). Conclusions While more studies found no evidence of increased risk of exclusive-vaping compared with non-use and evidence of comparable risk for exclusive-vaping and exclusive-smoking, the quality of the evidence limits conclusions. Without adequate assessment of exposure to vaping and smoking, findings cannot be attributed to behaviour as many who vape will have smoked and many who vape may do so at low levels. Study registration https://osf.io/rfx4q/. Supplementary Information The online version contains supplementary material available at 10.1186/s12884-024-06633-6.


Introduction
Smoking during pregnancy is harmful to maternal, fetal and child health; increases the risk of adverse birth outcomes such as preterm birth, low birthweight, stillbirth, and miscarriage [1]; and is a global public health issue [1,2].Effective smoking cessation interventions for pregnant individuals are urgently needed.Nicotine replacement therapy (NRT) is effective for smoking cessation in non-pregnant smokers [3]; however, it is not effective in controlled trials during pregnancy [4].This is probably due to low adherence and inadequate dosing [4]; nicotine is metabolised faster during pregnancy and standard dosing may be too low [5,6].
Vaping (i.e., use of electronic cigarettes) provides nicotine as an aerosol [7] and is distinct from traditional NRT, allowing tailored titration of nicotine and offering flavours and enjoyment [7][8][9].Consistent with the International Tobacco Control Policy Evaluation Project [10], throughout this review, we refer to these products using the term 'vaping' .Where we use the term 'smoking' we are referring to combustible tobacco products.Vaping is more popular for smoking cessation than traditional NRT [11,12].Cessation trials, in non-pregnant populations, have shown that vaping is more effective than NRT [13].Vaping is increasingly popular for smoking cessation and harm reduction in pregnancy [14,15] and one randomised controlled trial (RCT) showed vaping to be more effective than NRT for cessation in pregnancy when excluding those using non-allocated products [16].
Vaping has the advantage that it does not involve tobacco combustion, which is the primary source of harm from smoking cigarettes [7,17].Nicotine intake from vaping has the same concerns for the fetus as nicotine from NRT.It is plausible that nicotine could detrimentally affect human fetuses.Studies with nicotine-naïve animals have reported adverse effects of nicotine on fetal lung development [18,19].However, caution is needed in extrapolating animal findings, using forced chronic high doses of nicotine, to intermittent self-administered nicotine intake in humans [19].Systematic reviews and meta-analyses conclude that there is unclear evidence on whether the use of NRT during pregnancy is harmful to the fetus [20,21].A more recent study reported that the use of nicotine-based snuff in early pregnancy was associated with an increased risk of infant mortality; however, this study failed to consider the potential effects of smoking during the periods before and after the assessment [22].
There are also concerns about vaping ingredients other than nicotine [19].Vaping involves heating liquid which typically contains flavourings, propylene glycol and vegetable glycerine [7], and results in the formation of carcinogens and toxicants, including nitrosamines, volatile organic compounds (VOCs), polycyclic aromatic hydrocarbons (PAHs) and heavy metals, which are generally present at much lower levels than in smoking [12,[23][24][25].For the general adult population, at least in the short-to medium term, biomarker research suggests that vaping poses a small fraction of the risk of smoking [12,25,26].The most recent systematic review of studies examining evidence for the health impact of vaping in pregnancy, including 13 studies published up to February 2022, reported mixed and inconclusive findings and a call for more high-quality evidence [27].Over the last few years, there has been a proliferation of human studies on the health consequences of vaping during pregnancy and an updated review is urgently needed.We conducted a systematic review, with the principal aim of assessing evidence on health outcomes associated with exclusivevaping in pregnancy, compared with no use of nicotine and tobacco products and compared with smoking alone.

Methods
This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [28].The review protocol was registered with the Open Science Framework [29].

Eligibility criteria
We included primary, quantitative human studies, of any design, that reported on the health consequences of vaping during pregnancy and were limited to publications in peer reviewed journals in English.We excluded studies without full texts (e.g., abstract only).Although we sought all health outcomes, we anticipated including most of the important clinical outcomes for pregnant women, fetuses and infants identified in reviews of the health consequences of NTR and smoking [1,4,21], including miscarriage, stillbirth, preterm birth, birthweight, low birthweight, small for gestational age, admission to neonatal intensive care, caesarean section, congenital abnormalities and neonatal death.We also anticipated that biomarker studies would include most of the biomarkers of toxicants and carcinogens that have been assessed in studies of vaping among non-pregnant populations [12], including nitrosamines, VOCs, PAHs and heavy metals.

Data sources and search strategy
We searched MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Psy-cInfo, Maternity and Infant Care and the Cochrane Central Register of Controlled Trials.The searches had no start date and were conducted up to November 10th, 2023.To identify relevant systematic reviews, we also searched the Cochrane Protocols (Cochrane Library)

Study quality
We assessed study quality using the Mixed Methods Appraisal Tool (MMAT) [30].We chose the MMAT because it can be applied to all types of quantitative studies.The MMAT includes five criteria.For nonrandomized quantitative studies, the following criteria were used: 1. Were the participants representative of the target population?2. Were the measurements appropriate regarding both the outcome and intervention (or exposure)?3. Were there complete outcome data? 4. Were appropriate confounders accounted for in the design and analysis?5.During the study period, was the intervention administered (or exposure occurred) as intended?For RCTs, the following criteria were used: 1. Was randomisation appropriately performed?2. Were the groups comparable at baseline? 3. Were there complete outcome data? 4. Were outcome assessors blinded to the intervention provided? 5. Did the participants adhere to the assigned intervention?Two reviewers independently completed assessments and resolved discrepancies, involving a third reviewer if necessary.Calculating an overall score is discouraged; instead, as advised, we provide a table and summary of criterion ratings.

Analysis
Meta-analysis was not considered appropriate because for none of the outcomes were there sufficient highquality studies (i.e., at least three) [31].Outcomes were categorised as maternal or fetal/infant and presented narratively.Maternal outcomes are reported separately for pregnancy/postpartum outcomes and for biomarkers related to maternal exposure to toxicants and carcinogens.Fetal/infant outcomes are grouped to present similar outcomes together.Where available, effect sizes are presented in the tables.For each type of outcome a summary of findings is presented in the results.
When discussing study groups, 'exclusive vapers' refers to those just vaping, 'dual-users' denotes those both smoking and vaping, 'exclusive-smokers' refers to those just smoking (any combustible tobacco product, although in most cases only cigarette smoking was reported), and 'non-users' refers to those not using nicotine or tobacco products, unless otherwise stated.When presenting the results, we focused on evidence of the risk of adverse outcomes for exclusive-vaping compared with non-use or/ and compared with smoking.The risk of dual-use, compared with smoking, exclusive-smoking and non-use, is also reported but given less prominence as it is unclear how much people who vape and smoke are smoking and therefore findings are difficult to interpret.

Study selection
The search identified 1,563 articles.After duplicate removal, 1,291 records were screened for eligibility.Thirty-six full texts were reviewed and 25 studies were included (see Fig. 1.PRISMA flow diagram) [16,.In addition, one study was identified from hand-searching references cited in retrieved full texts [56], and one 'in press' article was identified [57] as a secondary analysis of data from one of the studies identified in the search [16].Therefore, a total of 26 studies, published between 2019 and 2023, were included.

Description of included studies
Table 1.presents the study aims, design, sample size, maternal characteristics, and outcomes of the included studies, including 765,527 women, with two further studies focusing on 67 stillbirths [44] and 83 infants [40].Table 2. presents the vaping and smoking groups and their associated characteristics.

Study design
One RCT (comparing vaping and NRT for smoking cessation in pregnancy, n = 1,095) [16], reported outcomes by randomisation group and when combining the whole sample who were using either vaping or NRT, irrespective of randomisation [57].We did not count this latter secondary analysis as a separate study as it analysed the same data as the main study.There were 23 cohort studies, including 17 retrospective studies (i.e., use of nicotine and tobacco products was assessed retrospectively [32,35,36,39,42,43,45,[47][48][49][50][51][52][53][54][55][56] and six prospective studies (i.e., product use assessed across time) [33,34,37,38,46].Fifteen cohort studies involved secondary data analysis of US data, including twelve from Pregnancy Risk Assessment Monitoring (PRAMS) data [32,35,36,42,43,49,50,[52][53][54][55][56] and three from the Population Assessment of Tobacco and Health (PATH) [38,39,45].We counted these secondary analyses as separate studies as, in cases where they assessed the same outcome, each study used a different set of data, with different sample sizes and with the studies varying not only in the years sampled (range: PRAMS 2016-2020, PATH 2011-2019) but also in inclusion criteria (e.g., two PRAMS studies restricted the data to infants with birth weights of 400g or higher) and in the covariates used.There were also two case-control studies [40,44].
The RCT initially compared safety outcomes for those allocated to the vaping and NRT arms [16] and then, in a secondary analysis, compared outcomes for those who were not smoking and who did or did not regularly use nicotine products (i.e., vaping or NRT, combined) during pregnancy [57].Four studies compared outcomes for those switching products [32,33,35,52].

Quality assessment
We rated the 23 cohort studies and two case-control studies against the MMAT criteria for quantitative non-randomised studies (Table 3).Overall quality was poor.All the studies were scored as zero for the criterion 'Were measurements appropriate regarding both the outcome and intervention (or exposure)?' and were scored as 'unclear' for 'During the study period, was the intervention administered (or exposure occurred) as intended?' .This is because none of the studies adequately measured exposure to nicotine and tobacco products; for example, through only measuring product use in late pregnancy or 'recently' and through not using biochemical verification.Eleven studies were considered to have unrepresentative samples.For the criterion 'Were appropriate confounders accounted for in the design and analysis?' , three studies included all vapers without controlling for smoking status and therefore were rated as zero [38,51,56] as smoking is likely to be the most important confounder.All studies were considered adequate for levels of missing data.One study was rated against the MMAT RCT criteria [16] and considered to have met all criteria except for intervention adherence.This was because of contamination; among participants reporting smoking abstinence, six of 39 in the vaping arm regularly used NRT and all 25 in the NRT arm regularly vaped.Other study limitations are referred to in the results section and/or summarised and commented on in the discussion section.

Maternal outcomes Pregnancy and postpartum outcomes
Six studies examined specific maternal pregnancy or postpartum outcomes [16,36,47,51,55,56, see Table 4].In addition, two studies included pregnancy outcomes in a composite measure [38,45] (see 'Other fetal and infant outcomes').In summary, there was no evidence of increased risk for exclusive-vaping compared with non-use for low gestational weight gain [55], postpartum depression [36] or for a composite of adverse outcomes (or for individual outcomes of hypertensive disorders, gestational diabetes or postpartum haemorrhage) [47], and increased risk of miscarriage (possibly a spurious finding due to a sample size of only 10, with three using non-nicotine vapes) [47].There was evidence of a similar risk for exclusivevaping vs exclusive-smoking for low gestational weight gain [55] and for a composite of adverse outcomes (and for individual outcomes) [47] and greater risk for exclusive-vaping for miscarriage [47].The findings for the latter two studies need to be treated with caution as they  simultaneously reported no significant difference in risk for exclusive-vaping and non-use.This implies that smoking does not pose an elevated risk, when it has been well established that smoking poses an increased risk [1], and therefore raises questions about the validity of their findings for vaping.One study observed that vapers (combining exclusive-vapers and dual-users) had a greater risk of depression symptoms during pregnancy than non-users or exclusive-smokers [51].Another study observed increased risk for high maternal blood pressure outcome, but not for gestational diabetes or depression, among those reporting any vaping during the last three months of pregnancy than among non-users [56].Neither of the latter two studies controlled for smoking status and in one study dual-users reported smoking more than exclusive-smokers [51].The RCT compared vaping and NRT, with no significant differences for a range of outcomes; adverse effects of vaping may be obscured by higher rates of smoking and high levels of vaping in the NRT group [16].When the RCT compared those abstinent from smoking and regularly vaping or using NRT with those not using these products, irrespective of trial arm, non-users had significantly more overall adverse outcomes and there were no significant differences for caesarean section rates [57].

Biomarkers of exposure
Two studies examined maternal exposure to biomarkers of toxicants and carcinogens during pregnancy and neither reported evidence of increased risk of vaping (see Table 5) [37,39].One reported that various toxicant and carcinogen urinary biomarkers were substantially lower for exclusive-vapers than for exclusive-smokers or dualuses [39], although without statistical tests, and the risk for exclusive-vaping vs non-use was not examined.Levels of the heavy metals lead and cadmium were similar across groups, as expected based on their half-lives.The other study reported that hair biomarkers of carcinogens were not significantly different among dual-users, nonusers and exclusive-smokers [37] but did not include exclusive-vapers [37].Both studies had very small sample sizes, lacked information on the level of exposure to vaping or smoking, and included few biomarkers compared with studies of non-pregnant populations [12,25], making it difficult to draw conclusions.

Fetal and infant outcomes
The most frequently assessed outcomes were key infant outcomes that have been shown to be detrimentally affected by smoking [1]; namely, preterm birth (PTB)/ gestational age (GA), small for gestational age (SGA), and low birth weight (LBW)/birth-weight (BW).Studies also assessed neurological measures, various other fetal and infant outcomes and composite outcomes.The effect sizes for fetal and infant outcomes are presented in Table 6.

Preterm Birth (PTB) and gestational age at birth (GA)
Ten studies reported PTB [16, 32, 42, 43, 47-50, 53, 54] and five reported GA [16,33,40,46,48].Nine studies compared exclusive-vapers and non-users and one compared non-users with a group combining exclusive-vapers and dual-users controlling for smoking status [48].Six of these studies observed no significant group differences in PTB rates [32,42,48,50,53,54] and four reported no significant group differences for GA [40,42,46,48].In one study this was the case irrespective of the frequency of vaping [54].Conversely, two studies observed significantly greater PTB rates for exclusive-vapers than for non-users [43,49].Additionally, one of these studies reported a significantly higher PTB prevalence for 'daily' exclusivevapers than for a group combining exclusive-smokers and non-users, but not for non-daily vapers [49].Another study found that compared with those who continued to vape, those who quit vaping during pregnancy did not have a significantly lower risk of preterm birth [32]; however, among those who did not smoke during the three months before pregnancy or in the last three months of pregnancy, those who quit vaping had a significantly lower risk of PTB.Three studies compared exclusive-vaping and exclusive-smoking; one observed a lower risk of GA for exclusive-vaping [46] and two observed a similar risk of PTB for exclusive-vaping and exclusive-smoking [43,50].The finding for one of the latter studies should be treated with caution as they also reported no absolute risk for PTB [50].One study had inconclusive results, observing no significant differences in GA for those switching between exclusive-smoking, exclusive-vaping and dual-use during pregnancy [33].The RCT found no significant differences in PTB or GA between the vaping and NRT arms [16].The RCT also found that, irrespective of trial arm, those who reported smoking cessation and the use of NRT or vaping in pregnancy had significantly fewer PTBs than did those reporting cessation and no use of these products [57]; GA was similar in these two groups.
Additionally, six studies compared dual-users with other groups.Five studies observed no significant differences in PTB rates between dual-users and non-users [32,42,50,53,54] and one observed similar GA for these groups [46].Three studies compared dual-use and exclusive-smoking and reported similar GA [46] and PTB prevalence [49,50].One of the latter studies also found that the prevalence of preterm births was similar for        dual-users and 'non-vapers' (combination of exclusivesmokers and non-users), irrespective of the frequency of vaping [49].One study compared exclusive-vaping and dual-use and reported similar GA [46].Finally, one study compared exclusive-vapers, exclusive-smokers, dualusers and non-users, as a whole, and found no significant difference in PTB rates [47].The RCT reported that, irrespective of trial arm, exclusive-smokers had rates of PTB and GA similar to those who dual-used smoking in combination with vaping or NRT [57].
To summarise the findings for PTB/GA, eight studies reported that exclusive-vaping did not have a significantly different risk than non-use [32,40,42,46,48,50,53,54] and two studies reported a significantly higher risk for exclusive-vaping [43,49].The finding for the latter two PRAMS studies is inconsistent with five of the above PRAMS studies which found no difference between the groups [32,42,50,53,54].This divergence in findings is most likely due to different analyses and inclusion criteria (see Table 1).One study reported that exclusive-vaping had a significantly lower risk than exclusive-smoking [46] and two observed no significant difference between the two groups [43,49], although one of the latter studies simultaneously found no difference between exclusivevaping and non-use, which leads us to question the validity of the findings.

Small for gestational age/mean birth centile
Small for gestational age (SGA) was reported in 12 studies [32,[34][35][36]42,43,47,49,50,[52][53][54] and mean birth centile (MBC) in one study (46).Eight of ten studies comparing SGA or MBC prevalence between exclusivevapers and non-users reported no significant differences [32,34,35,42,46,50,53,54]. In one of these studies, this was the finding irrespective of the frequency of vaping [54].Two studies observed a significantly higher SGA risk for exclusive-vapers [43,52].Consistent with this, one study observed that exclusive-vapers who became non-users by late pregnancy had significantly lower SGA risk than those who continued vaping, and comparable risk to non-users [52].Similarly, one study reported that, compared with non-users, dual-users who switched to exclusive-vaping had an elevated risk of SGA [35].Additionally, one study reported that, compared with a group combining exclusive-smokers and non-users, prevalence of SGA for exclusive-vapers was similar, irrespective of whether vaping was daily or less than daily [49].
Three studies compared exclusive-vaping and exclusive-smoking.The first study observed (healthily) significantly higher MBC for exclusive-vapers [46].The other two studies reported similar SGA rates for the two groups [43,50].A further study found that switching from exclusive-smoking to exclusive-vaping significantly reduced the risk of SGA so that it was similar to non-use [52].
Of nine studies comparing dual-use and non-use [32, 34-36, 42, 50, 52-54], six reported a significantly higher prevalence of SGA for dual-users [32,42,50,[52][53][54].Among four studies comparing dual-use and exclusive-smoking, two observed a similar risk of SGA [49,50], one observed comparable MBCs [46], and one found that switching from exclusive-smoking to dual-use had little effect on SGA risk [52].One study compared exclusive-vaping and dual-use and reported a lower MBW for dual-users [46].A further study reported a significant difference in rates of SGA when comparing exclusive-vapers, exclusive-smokers, dual-users and non-users, as a whole, although pairwise comparisons were not reported [47].One study showed that quitting vaping during pregnancy vs continuing was not significantly associated with a reduced risk of SGA when controlling for smoking during the three months before pregnancy or in the last 3 months of pregnancy [32].
In summary, for SGA/MBC, eight studies reported that exclusive-vaping did not have a significantly different risk than non-use [32,34,35,42,46,50,53,54] and two observed that exclusive-vaping had a higher risk [43,52].Similar to the findings for PTB/GA, the finding for the latter two 'PRAMS' studies is inconsistent with six of the above PRAMS studies which found no group differences [32,35,42,50,53,54].Two studies reported a significantly lower risk for exclusive-vaping than for exclusive-smoking [46,52] and two reported no significant difference for these two groups [43,50].The findings for one of these studies are problematic as they simultaneously observed no difference between exclusive-vaping and non-use.

Low birth weight (LBW)/birth-weight (BW)
Eleven studies reported LBW or BW [16, 32-34, 40, 42, 43, 46, 48-50].Among eight studies comparing exclusive-vaping and non-use, four reported similar BW [34,40,42,46] and four observed a higher likelihood of LBW for infants of exclusive-vapers [32,43,49,50].In one of these studies the association between exclusive-vaping and LBW was not significant when adjusting for GA or when restricting the analysis to full-term births, indicating that effects on LBW could be mediated by PTB (although the risk of PTB was not significantly associated with exclusive vaping -see above) [32].One of the studies reported a significantly higher prevalence of LBW for exclusive-vapers than for a group combining exclusive-smokers and nonusers, irrespective of whether vaping was daily or less than daily [48].
Among three studies comparing exclusive-vaping and exclusive-smoking, one found lower BW for exclusive smokers [46] and two reported similar LBW risk for the two groups [43,50].One study showed that quitting vaping during pregnancy vs continuing vaping was significantly associated with a reduced risk of LBW [32].However, when focusing the analysis on those who did not smoke during the three months before pregnancy, or in the last three months of pregnancy, this association was not significant.
Of three studies comparing dual-users and nonusers, one detected no significant group differences [34], one revealed significantly lower weights for infants of dual-users [42], and the third observed higher risk of LBW for dual-users [32].Three found similar risk of LBW for dual-users and exclusive-smokers [46,49,50].One study showed that babies of dualusers had significantly lower BW than exclusive-vapers [46].One study reported that vaping (combining exclusive-vapers and dual-users) was not associated with BW, compared with non-vapers, when adjusting for smoking patterns [48].A further study found no significant differences in BW for those switching between exclusive-smoking, exclusive-vaping and dual-use during pregnancy but found that those who switched from using any product to no product had infants who weighed significantly more [33].The RCT found that, compared with the NRT arm, babies in the vaping arm had a significantly lower risk of LBW, most likely due to lower smoking [16].Additionally, irrespective of trial arm, those who reported smoking cessation and the use of NRT or vaping during pregnancy had similar BWs and LBWs to those reporting cessation and no use of these products and significantly greater BWs than those reporting smoking [57].BWs and rates of LBWs were similar among those who reported smoking and those reporting dual-use of smoking and vaping or NRT.

Infant neurobehavioural and neuropathological outcomes
Three studies reported infant neurological outcomes [40,41,44] and compared exclusive-vaping and non-use.The first study observed that abnormal reflex scores were significantly higher and motor maturity scores were significantly lower for infants exposed to vaping [40].The second reported that, among cases of sudden intrauterine unexplained deaths, adverse neuropathological brainstem outcomes (pulmonary hypoplasia, pFn hypoplasia) were more common for infants of exclusive-vapers [44], although neither samples sizes nor statistical tests were reported.No significant differences in risk were found for exclusive-vaping vs non-use for self-regulation scores [40] or relative frequency of mouth movements [41].The latter study also observed that mouth movements significantly (and healthily) declined from 32 to 36 weeks gestation for non-exposed fetuses, but not for the fetuses of exclusive-vapers or exclusive-smokers.However, there was a tendency for mouth movements to reduce in the exclusive-vaping group although this group was too small (n = 14) to have a good chance of finding a significant difference.
All three studies reported similar levels of adverse neurological outcomes for exclusive-vaping and exclusive-smoking, for the following outcomes: reflex, motor maturity and self-regulation scores [40], relative frequency of mouth movements [41], and neuropathological brainstem outcomes [44].The finding for self-regulation needs to be treated with caution as they simultaneously reported no heightened risk for self-regulation for exclusive-vaping compared with non-use [40].One study observed that adverse neuropathological brainstem outcomes were more common for infants who were exposed to dual-use compared with infants of non-users and were similar among infants exposed to exclusive-smoking, dual-use or exclusive-vaping [44].
In summary, among three small studies of neurological outcomes, for at least one outcome, two reported exclusive-vaping having a similar risk to non-use [40,41] and two reported higher risk for exclusive-vaping [40,44].They all reported that exclusive-vaping had a similar risk to exclusive-smoking for all outcomes.These studies had the advantage that they all biochemically verified smoking status and two of the studies assessed the strength of nicotine in the vapes [40,41].

Other fetal and infant outcomes and composite birth outcomes
Eight studies reported other fetal and infant outcomes or composite outcomes [16,33,38,40,[45][46][47]56].Among three studies assessing neonatal intensive care unit (NICU) admissions [16,33,46], one observed similar admissions for babies of exclusive-vapers, dualusers, exclusive-smokers, and non-users [46].The second observed no significant differences in admissions or infant respiratory distress for those switching between exclusive-vaping, dual-use and exclusive-smoking during pregnancy [33].The RCT found similar congenital abnormalities and NICU admissions for the NRT and vaping arms [16].When comparing dual-users and smokers, irrespective of trial arm, rates of congenital abnormalities were not significantly different [57].
Nanninga and colleagues examined hospital admissions in the first year of life when comparing babies born to exclusive-vapers, exclusive-smokers, dual-users and non-users, as a whole, and reported no significant difference [47].Lin et al. found no significant difference in the rates of fetal death between a group combining exclusive-vapers and dual-users vs non-users, controlling for smoking status [45].This study also observed that, compared with 'other vaping flavours' , menthol/mint was significantly associated with fetal death but was not associated with a composite of adverse birth outcomes; however, rates of smoking in the different flavour groups were not considered.
Two 'PATH' studies reported no significant difference in composite measures of adverse birth outcomes for a combination of exclusive-vapers and dual-users compared with non-users [38,45], (one study did not control for smoking status [38]) and another found no difference for such a composite when comparing babies of exclusive-vapers, exclusive-smokers, dualusers and non-users, as a whole [47].Another study observed significantly higher odds of at least one adverse birth outcome among those reporting any vaping during the last three months of pregnancy than among those who did not, although they did not control for smoking status [56].
A further study observed similar infant head circumferences for infants of exclusive-vapers, exclusive-smokers and non-users [40].One study found that APGAR scores were identical for babies of exclusive-vapers, dual-users, exclusive-smokers and non-users [46].In summary, there was no evidence of an increased risk of exclusive-vaping compared with non-use for NICU admissions [46] or APGAR scores [46], hospital admissions [47], fetal death [45], a composite measures of adverse birth outcomes [47] or infant head circumferences [40].There was evidence of similar risk for exclusive-vaping and exclusive-smoking for NICU admissions and APGAR scores [46], hospital admissions [47], a composite measures of adverse birth outcomes [47] and infant head circumferences [40].Notably, for three of these studies [40,46,47] the evidence is questionable as they simultaneously found no increased risk for exclusive-vaping compared with non-use and found similar risk for exclusive-vaping and exclusive-smoking, for the same outcomes.

Discussion
This review reports on 26 studies examining vaping and health outcomes for pregnant and postpartum women, their fetuses and infants.It focuses on the comparison of exclusive-vaping with non-use of nicotine or tobacco and with exclusive-smoking.The results are complex to interpret as the quality of the studies, except the RCT, was rated as poor, the types of groups compared varied greatly, and for most outcomes there is mixed evidence.Therefore, consistent with the most recent previous review on this topic [27], the findings are inconclusive.
To aid interpretation, we summarise the findings across all studies.For studies comparing exclusive-vaping and non-use, more studies reported no increased risk than reported increased risk.For comparisons of exclusivevaping and exclusive-smoking, most evidence indicated a similar risk for both groups.Regarding dual-use, for the key fetal and infant outcomes there was the most evidence for dual-use having a comparable risk to exclusive-smoking and presenting an increased risk compared with exclusive-vaping and non-use.Few studies examined dual-use for other outcomes.As none of the studies reported both the frequency and duration of smoking, it is not possible to interpret the implications of the findings for the risks of vaping.Most pregnant women who vape do so to stop smoking or reduce smoking [58].There is some evidence that vaping may be effective for smoking cessation during pregnancy [16] and effective interventions are needed to help all pregnant people stop smoking, including dual-users of smoking and vaping.
Confidence in the findings is constrained by the many limitations of the studies.Most importantly, none of the studies, except the RCT, adequately assessed exposure to nicotine and tobacco products, especially cigarette smoking.For example, the largest and most rigorous cohort studies used the PRAMS dataset (12 of the included studies), which relies on retrospective, self-reported product use in late pregnancy; therefore, the potential influence of product use during early or mid-pregnancy could not be considered and there was no biochemical verification.Relying on self-reports and lack of assessment of dose may lead to misclassification of exposure, affecting associations with outcomes [59].Thus, where the risk of exclusive-vaping was reported, as nearly all pregnant women who vape are likely to be current or former smokers [14,[60][61][62] it is possible that this heightened risk is largely due to high levels of smoking at times beyond the assessment period or concurrent unreported smoking.Additionally, even if smoking were considered, without detailed information on levels of vaping it is not possible to say if more intense vaping poses a risk where no risk of exclusive-vaping was found.These limitations also apply to studies examining switching between products.A further limitation is that, although the 12 PRAMS studies analysed different data sets, with different sample sizes, they had overlapping data, with the same pregnancies included in multiple studies (e.g., they all included data for 2016), which could bias the results.However, for any one outcome, the studies do not always agree (e.g., the findings diverge for the comparison of exclusive-vaping and non-use for the key outcomes of PTB/GA, SGA/ MBC and LBW/BW), due to differences in analysis and inclusion criteria, which supports the approach of including them as separate studies.
Other notable limitations included that many studies had small to very small sample sizes for the groups of interest, they did not include the key comparisons of exclusive-vaping with exclusive-smoking and non-use of vaping and smoking and had non-representative samples.The findings of similar risk of exclusive-smoking and exclusive-vaping for six studies, for some outcomes, need to be treated with caution, as they simultaneously found no significantly increased risk for exclusive-vaping compared with non-use [40, 45-47, 50, 54].This would imply that smoking does not pose an increased risk, which has been established beyond doubt for pregnancy outcomes [1] and raises questions about the validity of their findings on vaping.There were only two studies of biomarkers with small sample sizes, limited study groups and a narrow range of biomarkers.
The sole RCT warrants separate comment.The usefulness of the analysis comparing the randomised groups (vaping vs NRT) is limited for our purposes because most participants continued to smoke and, among those who ceased smoking, only some used the assigned products and some used products assigned to the comparison group.The authors subsequently published a secondary analysis, comparing participants who did or did not use nicotine products (the NRT and vaping groups were combined because there was no indication of differences between them at baseline) regularly during pregnancy, irrespective of randomisation [57].This secondary analysis reported no evidence of risk for exclusive-vaping, and comparable risk for dual-use (smoking and vaping or NRT) and exclusive-smoking for some outcomes.As the groups were not randomised, unmeasured confounders could influence the findings, but less so than with cohort studies, where groups could differ substantially on factors such as previous smoking levels and when they stopped smoking.In the RCT, participants were reasonably homogenous, in that they smoked daily during early pregnancy, sought help with quitting, were not using nicotine products when recruited, and completed detailed assessments on product use, including biochemical verification, that the cohort studies lacked.The findings are limited in that there were only 25 individuals in the group not using NRT or vaping, and the separate effects of vaping were not examined.

Implications of the results
In line with recommendations for research on other health effects of vaping [12], large, longitudinal, representative, naturalistic studies examining the risk of vaping are needed, primarily, with women who exclusively vape throughout pregnancy compared with those who have never used nicotine and tobacco products, and with those who exclusively smoke.In addition, studies are needed to examine the risks of vaping among women who smoke and switch to vaping at different stages of pregnancy, when controlling for previous smoking levels, compared with those who smoke or vape throughout pregnancy and those who use no products.Studies also need to identify the risks in women who vape and have never smoked.This research ideally needs to satisfy the following criteria: • Rigorously assesses self-reports of smoking (of all types of combustible tobacco product) and vaping levels, including the frequency, duration and recency of usage, the type of product used, and nicotine strength.• Assesses the level of usage of all nicotine and tobacco products (e.g., including NRT) • Includes biochemical verification of status as an exclusive-vaper or as a non-user of nicotine and tobacco products.• Conducts assessments at multiple time-points, at pre-pregnancy, during each trimester of pregnancy, in postpartum and beyond.• Assesses a range of potential confounders of the outcomes, including self-reports of second-hand exposure to smoking and vaping, as well as maternal age, ethnicity, socio-economic status and gestation at the time of the assessments.
Additionally, the risks of vaping need investigating in randomised trials of smoking cessation in pregnancy.Although large cohort studies and RCTs will provide the best data to assess the safety of vaping during pregnancy, these studies are time-and resource-intensive.In the absence of these data from rigorous studies, larger and more rigorously designed biomarker studies are needed to assess the potential harms of vaping during pregnancy.Cross-sectional biomarker studies offer insight into exposure from naturalistic use patterns.Longitudinal research, especially with extended follow-up, is valuable for assessing long-term changes in biomarker exposure, especially among exclusive-vapers with sustained usage, and may be especially important for biomarkers with longer half-lives.Besides the criteria listed above, biomarker studies need to include a broad selection of biomarkers, adequate assessment of exposure to environmental toxins that might affect biomarkers (e.g., occupational exposure to acrolein, air pollution), and consideration of the half-lives of biomarkers.
As noted previously [12], there is a need for standardisation of methodologies among studies exploring the health risks of vaping, including in pregnancy, to aid synthesis and comparisons across studies.Standardisation is especially needed in the assessment of the levels of vaping and smoking, and in the type of maternal, fetal and infant outcomes assessed, including biomarkers of exposure.Greater user engagement and involvement in this research is needed.Pregnant women who currently or previously vape or smoke can help to design research to ensure it is addressing relevant questions, to assist with interpreting findings and to aid dissemination.

Strengths and limitations
The strengths of this review include the use of broad inclusion criteria, the identification of a large number of recent studies covering a wide range of outcomes, with several researchers involved in screening and data extraction, and the inclusion of a thorough quality assessment.Limitations include the exclusion of non-English language studies and it only being possible to present a narrative review rather than a meta-analysis, as there were insufficient high-quality studies.

Conclusions
Recommendations around the use of vaping in pregnancy for harm reduction can be informed by studies examining the evidence for the risks of vaping for the fetus, mother, and infant.The evidence for the effects of smoking on these outcomes is well established for non-pregnant smokers versus non-smokers. 1 A challenge with research establishing health consequences of vaping in pregnancy is that most vapers are former or current smokers and in the studies reporting risks of vaping it is not clear whether the harms were caused by smoking.A related challenge is the uncertainty inherent in self-reporting of vaping and smoking, particularly in this population, and the lack of detailed assessments, such as the amount, frequency and duration of use and composition, including nicotine strength, of products.The evidence is also uncertain from studies reporting no risk of vaping because the levels and content of vaping are not known.Overall, more studies found no evidence of increased risk for exclusive-vaping vs non-use than detected a risk, and more observed comparable risk for exclusive-vaping and exclusive-smoking than observed lower risk for exclusive vaping.These two sets of observations are somewhat contradictory and are likely due to the poor quality of the evidence, which continues to limit confidence in conclusions.Overall, this review confirms the findings of a previous review [27] that the studies are of poor quality, which disallows the use of meta-analysis, and the findings are inconclusive.

Fig. 1
Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram

Table 1
Study aim, design, maternal characteristics, and outcomes

Table 1 (continued) Author, date, setting, country, timescale Study aim Design and sample size Maternal age (years) Ethnicity/race Socioeconomic status/education/ income Time of assessment in pregnancy/ postpartum Covariates assessed Outcomes
gain Table 1 (continued) NR not reported, SD standard deviation, BMI body mass index, PTB pre-term birth, GA gestational age, BW birth weight, LBW low birth weight, SGA small for gestational age

Table 2
Vaping and smoking groups and associated characteristics

definition: % (n) Biochemical validation Dependence measures Other smoking and vaping characteristics reported a Second-hand exposure
NRTable 2 (continued) Author/date Study groups, definition: % (

definition: % (n) Biochemical validation Dependence measures Other smoking and vaping characteristics reported a Second-hand exposure
NR not reported, CPD cigarettes per day, NRT nicotine replacement therapy a Frequency and duration of vaping/smoking, product type/dose/ flavours, use of other nicotine or tobacco products

Table 3
[57]ity assessment using Mixed Methods Appraisal Tool (MMAT)[30]Were the participants representative of the target population?3.2 Were measurements appropriate regarding both the outcome and intervention (or exposure)?3.3 Were there complete outcome data?3.4Wereapropriateconfoundersaccounted for in the design and analysis?3.5 During the study period, was the intervention administered (or exposure occurred) as intended?cSecondaryanalysis of Hajek et al. 2022[16], reported by Pesola and colleagues[57]was not separately assessed for quality 1 = criterion met, 0 = criterion not met, C = Cannot tell if criterion has been met a Randomised controlled trial criteria 2.1 Was randomisation appropriately performed?2.2 Were the groups comparable at baseline?2.3 Were there complete outcome data?2.4 Were outcome assessors blinded to the intervention provided?2.5 Did the participants adhere to the assigned intervention?b Quantitative non-randomised criteria 3.1

Table 4
Findings for pregnancy and postpartum outcomes

Table 5
Findings for biomarkers outcomes

Table 6
Findings for fetal and infant outcomes

Table 6
(continued) NS not significant, SD standard deviation, NRT nicotine replacement therapy, aPR adjusted prevalence ratio, OR odds ratio, aOR adjusted odds ratio, aRR adjusted risk ratio